Molecular binding thermodynamics of spherical guests by β-cyclodextrins bearing aromatic substituents

Article abstract of DOI:10.1016/j.tca.2013.11.021

The molecular binding behaviors of two β-cyclodextrin (β-CD) derivatives bearing 1,2,3-triazole moieties, i.e. mono-6-deoxy-6-{4-(8- oxymethylquinolino)[1,2,3]triazolyl}-β-CD (1) and mono-6-deoxy-6-{4-(8- oxymethylnaphthol)[1,2,3]triazolyl}-β-CD (3), and their analogs without 1,2,3-triazole moieties, i.e. mono-6-deoxy-6-(8-oxymethylquinolino)-β-CD (2) and mono-6-deoxy-6-(8-oxymethylnaphthol)-β-CD (4) toward spherical guests (±)-borneol and (±)-camphor were investigated to elucidate how substituent moiety of host affects the binding abilities by 2D NMR as well as microcalorimetric titrations in aqueous phosphate buffer solution (pH 7.20) at 298.15 K. The binding modes of host-guest interactions obtained from 2D NMR displayed that host CDs without triazole moieties gave better induce-fit efficiency between hosts and guests, leading to stronger binding abilities. Thermodynamically, the inclusion complexation was driven by enthalpy with the stoichiometry of 1:1. Another factor contributed to the enhanced binding abilities was the enthalpy gain with the smaller entropy loss.

Full text of DOI:10.1016/j.tca.2013.11.021

Thermochimica Acta 576 (2014) 18–26
Contents lists available at ScienceDirect
Thermochimica Acta
journal homepage: www.elsevier.com/locate/tca
Molecular binding thermodynamics of spherical guests by
ˇ-cyclodextrins bearing aromatic substituents
∗
Nan Li, Yong Chen, Ying-Ming Zhang, Li-Hua Wang, Wen-Zhao Mao, Yu Liu
Department of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Collaborative Innovation Center of Chemical Science
and Engineering, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 September 2013
Received in revised form
The molecular binding behaviors of two ˇ-cyclodextrin (ˇ-CD) derivatives bearing 1,2,3-triazole moieties,
i.e. mono-6-deoxy-6-{4-(8-oxymethylquinolino)[1,2,3]triazolyl}-ˇ-CD (1) and mono-6-deoxy-6-{4-(8-
oxymethylnaphthol)[1,2,3]triazolyl}-ˇ-CD (3), and their analogs without 1,2,3-triazole moieties, i.e.
mono-6-deoxy-6-(8-oxymethylquinolino)-ˇ-CD (2) and mono-6-deoxy-6-(8-oxymethylnaphthol)-ˇ-
CD (4) toward spherical guests (± )-borneol and (± )-camphor were investigated to elucidate how
substituent moiety of host affects the binding abilities by 2D NMR as well as microcalorimetric titrations
in aqueous phosphate buffer solution (pH 7.20) at 298.15 K. The binding modes of host–guest interac-
tions obtained from 2D NMR displayed that host CDs without triazole moieties gave better induce-fit
efficiency between hosts and guests, leading to stronger binding abilities. Thermodynamically, the inclu-
sion complexation was driven by enthalpy with the stoichiometry of 1:1. Another factor contributed to
the enhanced binding abilities was the enthalpy gain with the smaller entropy loss.
2
1 November 2013
Accepted 22 November 2013
Available online 1 December 2013
Keywords:
ˇ-Cyclodextrin
Thermodynamic
Self-inclusion
Borneol
Camphor
© 2013 Elsevier B.V. All rights reserved.
1
. Introduction
the effects of different conformation on binding abilities of ˇ-CD
derivatives from the viewpoints of binding geometry and binding
Cyclodextrins (CDs) are cyclic oligosaccharides, formed from ␣-
thermodynamics.
1
,4 glucosidic bonds of a number of glucose units. Due to their
hydrophilic outer surface and hydrophobic inner cavity, they offer
the advantage of encapsulating various organic guests within their
hydrophobic cavities to form host–guests complexes through the
contribution of many intermolecular weak interactions, such as van
der Waals, hydrophobic, hydrogen-bonding, dipole–dipole, and
electrostatic interactions [1–4]. Moreover, introduction of diverse
substituents may alter both the physicochemical properties of the
CDs and the binding ability between CDs and guest molecules
2
. Experimental
2.1. Materials
All chemicals were used as reagent grade unless noted. ˇ-CD
was recrystallized twice from water and dried in vacuo at for
4 h. Camphor and borneol enantiomers were commercially avail-
able and used as received. Phosphate buffer solution of pH 7.20
2
[
5–7]. Therefore, great efforts have been put into designing and
developing of novel CD derivatives. In addition, “click chemistry”
8] was widely studied in various fields, particularly in design-
(
(
I = 0.1 M, 3% DMSO) was used for ITC experiments. Mono[6-O-
p-toluenesulfonyl)]-ˇ-CD (6-OTs-ˇ-CD) 7 was prepared by the
[
reaction of native ˇ-CD with p-toluenesulfonyl chloride in NaOH
aqueous solution in ca. 10% yield [12]. 6-Deoxy-6-azido-ˇ-CD 8
was prepared according to the literature procedure [13]. Crude DMF
was stirring in CaH for three days and then distilled under reduced
pressure prior to use.
ing new molecules and macromolecules under very mild reaction
conditions and high yield [9,10]. In the present work, we synthe-
sized a series of quinoline- and naphthol-modified ˇ-CD derivatives
with and without triazole moieties (Fig. 2), and investigated their
binding behaviors toward (± )-borneol and (± )-camphor (Fig. 1),
which are bicyclic terpenoids possessing the advantages of biolog-
ical functions such as antibacterial, antispasmodic, choleretic, and
tranquilizing effects [11]. It was our special interest to examined
2
2.2. Synthesis of 8-propargyloxynaphthalene (6)
A mixture of 1-naphthol 5 (2.4 g, 0.015 mol), K CO3 (6.2 g,
2
0
3
.045 mol) and propargyl bromide (80%, w/w solution in toluene,
.6 mL, 0.045 mol) in 40 mL of acetone was refluxed overnight.
∗ Corresponding author.
E-mail address: yuliu@nankai.edu.cn (Y. Liu).
Insoluble precipitates were removed by filtration, and the filtrate
was evaporated in vacuo. The residue was dissolved in CH Cl2
2
0
040-6031/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.tca.2013.11.021

N. Li et al. / Thermochimica Acta 576 (2014) 18–26
19
Fig. 1. Structures of guest molecules.
Fig. 2. Structures of host molecules.
(
100 mL), and the organic layer was extracted with 1 M HCl solu-
2.4. Synthesis of mono-6-deoxy-6-(8-oxymethylnaphthol)-ˇ-CD
(4)
tion (2× 50 mL) and brine. The yellow solution was dried under
reduced pressure and further purified by flash column chromatog-
raphy using PE/CH Cl (10:1, v:v) as eluent to give the product as a
colorless oil with a yield of 79% (R = 0.4). H NMR (400 MHz, CDCl ,
TMS, ppm): ı = 2.55 (t, J = 2.4 Hz, 1H; H of CH
Anhydrous K CO3 (0.47 g, 3.0 mmol) was added to a solution
2
2
2
1
of 8-hydronaphthalene (516 mg, 3.0 mmol) in dry DMF (12 mL).
The mixture was stirred for 2 h at room temperature under nitro-
gen. Then, 6-OTs-ˇ-CD 7 (1.9 g, 1.5 mmol) in dry DMF (20 mL) was
f
3
C
), 4.91 (d, J = 2.4 Hz,
2
(
H; H of CH
t, J = 8.0 Hz, 1H; H of naphthalene), 7.45–7.53 (m, 3H; H of naph-
thalene), 7.81 (dd, J = 6.2, 3.2 Hz, 1H; H of naphthalene), 8.32–8.24
C CH2 ), 6.95 (d, J = 7.6, 1H; H of naphthalene), 7.39
(
5
m, 1H; H of naphthalene). Anal. Calcd. for C13H10O: C, 85.69%; H,
.53%. Found: C, 85.40%; H, 5.73%. EI-MS: 182 [M+H] .
+
2
.3. Synthesis of mono-6-deoxy-6-{4-(8-oxymethylnaphthol)
[1,2,3]triazolyl}-ˇ-CD (3)
8
-Propargyloxynaphthalene 6 (328 mg, 1.80 mmol) in 15 mL of
THF was added to a solution of CuSO ·5H O (600 mg, 2.40 mmol)
4
2
and mono-6-deoxyl-6-azido-ˇ-CD 8 (1.39 g, 1.20 mmol) in 35 mL of
◦
water. The mixture was kept at 50 C for 10 min, and then sodium
ascorbate (1.42 g, 7.20 mmol) was added. The color of the mixture
◦
turned orange immediately. Then, the mixture was heated at 50 C
under an atmosphere of N2 overnight. After cooled to room tem-
perature, insoluble precipitates were removed by filtration, and the
filtrate was evaporated in vacuo. The residue was dissolved in a
small amount of water, and washed with 300 mL of acetone for
at least three times. After separation by column chromatography
(
silica gel) using n-PrOH:H O:NH ·H O (6:3:1, v:v:v) as eluent, 3
2
3
2
1
was obtained as a white solid with a yield of 70% (R = 0.4). H NMR
f
(
400 MHz, DMSO-d , ppm) ı = 3.65 (dd, J = 40.2, 19.4 Hz, 24H; C2-6
6
H of ˇ-CD), 4.54 (dd, J = 41.9, 20.9 Hz, 6H; O-6 H of ˇ-CD), 4.96–4.78
m, 7H; C-1 H of ˇ-CD), 5.30 (s, 2H; H of CH2 ), 5.97–5.62 (m,
(
1
7
4H; O-2, 3 H of ˇ-CD), 7.19 (d, J = 7.7 Hz, 1H; H of naphthalene),
.55–7.41 (m, 4H; H of naphthalene), 7.87 (d, J = 8.2 Hz, 1H; H of
naphthalene), 8.11 (d, J = 8.0 Hz, 1H; H of naphthalene), 8.28 (s,
Fig. 3. Microcalorimetric titration of host 1 with (−)-borneol in phosphate buffer
solution (pH = 7.20, I = 0.1 M, 3% DMSO) at 298.15 K. (a) Raw data for sequential
1
H; H of triazole). Anal. Calcd. for C55H79N O ·2H O: C, 47.93%;
3
35
2
25 injections (10 ␮L/injection) of (−)-borneol solution (2.00 mM) into host 1 solu-
H, 6.07%; N, 3.05%. Found: C, 47.90%; H, 6.27%; N, 3.12%. ESI-MS:
tion (0.094 mM). (b) Apparent reaction heat obtained from the integration of the
calorimetric traces.
+
1
364 [M+H] .

2
0
N. Li et al. / Thermochimica Acta 576 (2014) 18–26
◦
added dropwise with stirring, and the mixture was heated to 80 C
for 24 h. The resultant solution was evaporated under a reduced
pressure to give yellow powder, which was dissolved in a mini-
mum amount of hot water, and then the solution was poured into
acetone (200 mL). After separation by column chromatography (sil-
ica gel) using n-PrOH:H O:NH ·H O (6:3:1, v:v:v) as eluent, 4 was
ITC experiments were performed in aqueous phosphate buffer solu-
tion (pH 7.20, I = 0.1 M) at atmospheric pressure and 298.15 K, and
3% DMSO was added into the phosphate buffer to increase the sol-
ubility of hosts 3 and 4. All solutions were degassed by a Thermo
Vac accessory before titration experiments. Each microcalorimetric
titration experiment consisted 25 successive injections of a con-
stant volume (10 ␮L/injection) of guest solution into the reaction
cell (1.4227 mL) charged with host solution in the same buffer. Typ-
ical titration curves were shown in Fig. 3. Each titration of guest
molecules into the sample cell gave a reaction heat caused by the
formation of inclusion complex between CDs and guest molecules.
The reaction heat decreased after each injection of guest molecules
because less and less CDs were available to form inclusion com-
plexes. The dilution heat of host solution when added to the pure
buffer solution in the absence of CDs was determined in each run.
The dilution heat determined in these control experiments were
subtracted from the apparent reaction heat measured in titration
experiments to give the net reaction heat.
2
3
2
1
obtained as a white solid with a yield of 20% (R = 0.4). H NMR
f
(
400 MHz, DMSO-d , ppm) ı = 3.64 (dd, J = 54.7, 25.1 Hz, 27H; C2-6
6
H of ˇ-CD), 4.45 (dd, J = 39.5, 22.5 Hz, 6H; O-6 H of ˇ-CD), 4.86 (t,
J = 30.2 Hz, 7H; C-1 H of ˇ-CD), 5.75 (d, J = 30.0 Hz, 14H; O-2, 3H of ˇ-
CD), 6.96 (d, J = 7.4 Hz, 1H; H of naphthalene), 7.36–7.57 (m, 4H, 1H;
H of naphthalene), 7.86 (d, J = 6.5 Hz, 1H; H of naphthalene), 8.19 (d,
J = 6.9 Hz, 1H; H of naphthalene). Anal. Calcd. for C52H76O35·4H O:
2
C, 46.85%; H, 6.35%. Found: C, 47.10%; H, 6.26%. ESI-MS: 1283
+
[
M+Na] .
2.5. Microcalorimetric titration
The net heat in each run was analyzed by using “one set of
binding sites” model with ORIGIN software which provided by
Microcal VP-ITC titration microcalorimeter allows us to simulta-
neously determine the binding constant and the enthalpic change
from a single titration curve. The VP-ITC instrument was calibrated
chemically by the measurement of the complexation reaction of
ˇ-CD with cyclohexanol, and the obtained thermodynamic data
were in good agreement (error < 2%) with the literature data. All
Microcal Inc. to determine the binding stoichiometry (N), binding
◦
constant (K ), and reaction enthalpic changes (ꢀH ) from the titra-
S
tion curve. Knowledge of the binding constant (K ) and the reaction
S
◦
enthalpic changes (ꢀH ) enabled the calculation of standard Gibbs
Fig. 4. ROESY spectrum of host 4 in D2O with a mixing time of 280 ms at 298.15 K. (For interpretation of the references to color in this figure legend, the reader is referred to
the web version of this article.)

N. Li et al. / Thermochimica Acta 576 (2014) 18–26
21
Table 1
Complex stability constants (KS/M ), enthalpic changes (ꢀH ), entropic changes (TꢀS ) and Gibbs free energy changes (ꢀG ) for 1:1 intermolecular complexation of
± )-borneol and (± )-camphor with host CDs in phosphate buffer solution (pH 7.20, I = 0.1 M, 3% DMSO) at 298.15 K.
−
1
◦
◦
◦
(
KS (M 1
−
)
ꢀG (kJ mol
◦
−1
)
ꢀH (kJ mol
◦
−1
)
TꢀS (kJ mol
◦
−1
)
Guests
Hosts
2
3
3
3
3
(−)-Borneol
(+)-Borneol
(−)-Camphor
(+)-Camphor
ˇ-CD
(96.36 ± 3.54) × 10
(15.86 ± 0.28) × 10
(22.31 ± 0.62) × 10
(10.08 ± 0.35) × 10
(34.89 ± 0.84) × 10
−22.73 ± 0.18
−23.97 ± 0.04
−24.82 ± 0.07
−22.85 ± 0.09
−25.93 ± 0.06
−20.81 ± 0.98
−25.80 ± 0.18
−29.64 ± 0.17
−23.09 ± 0.04
−27.97 ± 0.21
1.93
−1.82
−4.81
−0.24
−2.03
1
2
3
4
2
3
3
3
3
ˇ-CD
(62.69 ± 3.07) × 10
(15.74 ± 0.18) × 10
(19.04 ± 0.00) × 10
(10.23 ± 0.01) × 10
(40.34 ± 2.28) × 10
−21.67 ± 0.12
−23.95 ± 0.03
−24.43 ± 0.00
−22.89 ± 0.03
−26.28 ± 0.14
−32.70 ± 0.68
−25.04 ± 0.11
−31.91 ± 0.45
−21.11 ± 0.11
−25.20 ± 1.40
−10.97
−1.08
−7.48
1.55
1
2
3
4
1.08
2
2
2
2
2
ˇ-CD
(23.64 ± 2.37) × 10
(47.76 ± 0.78) × 10
(52.59 ± 1.16) × 10
(26.18 ± 0.70) × 10
(83.24 ± 5.70) × 10
−19.24 ± 0.25
−21.00 ± 0.04
−21.24 ± 0.05
−19.51 ± 0.07
−22.37 ± 0.17
−26.70 ± 1.29
−18.02 ± 0.88
−20.69 ± 0.33
−15.49 ± 0.41
−19.27 ± 0.27
−7.45
2.97
0.55
4.02
3.10
1
2
3
4
2
2
2
2
2
ˇ-CD
(23.77 ± 0.66) × 10
(35.54 ± 0.96) × 10
(42.70 ± 3.58) × 10
(31.26 ± 0.59) × 10
(57.19 ± 1.62) × 10
−19.27 ± 0.07
−20.27 ± 0.07
−20.71 ± 0.21
−19.95 ± 0.05
−21.44 ± 0.07
−22.58 ± 1.24
−19.28 ± 0.01
−25.89 ± 1.29
−16.77 ± 0.02
−22.07 ± 0.34
−3.30
0.99
1
2
3
4
−5.15
3.19
−0.63
Fig. 5. ROESY spectrum of 2/(−)-borneol ([2] = [(−)-borneol] = 1.0 mM) in D2O (3% DMSO) with a mixing time of 280 ms at 298.15 K. (For interpretation of the references to
color in this figure legend, the reader is referred to the web version of this article.)

2
2
N. Li et al. / Thermochimica Acta 576 (2014) 18–26
◦
◦
free energy changes (ꢀG ) and entropic change (ꢀS ), according to
equation
but positive ICD signals, like that of host 1. These weak positive ICD
signals indicated that the side arms of hosts 3 and 4 may also be
located distant from the narrow opening of ˇ-CD cavity. In fluo-
rescence experiments, the fluorescence intensity of hosts 1, 3, or 4
slightly changed, but the shape of emission peak almost unchanged,
after the addition of guest molecules, indicating the conformation
of hosts 1, 3, or 4 was maintained upon guest complexation. How-
ever, both the shape and intensity of the emission peak of host 2
showed the obvious changes with the addition of guest molecules,
indicating that host 2 may undergo a conformational change upon
guest complexation.
◦
◦
◦
ꢀ
G = −RT ln K = ꢀH − TꢀS
S
where R is the gas constant and T is the absolute temperature.
To check the accuracy of calculated thermodynamic quantities,
we carried out several independent titration runs to afford self-
consistent thermodynamic parameters, and their average values
were listed in Table 1.
3
. Results and discussion
3.1. Circular dichrosim spectra and fluorescence emission spectra
3.2. 2D NMR
Generally, the proximity of an achiral chromophore to CD cavity
2D NMR spectroscopy is an essential method for the investi-
gation of interactions between CDs and guest molecules, because
two protons which are closely located in space can produce
an NOE cross-peak between the relevant protons in NOESY or
ROESY spectra. Moreover, 2D ROESY experiment is suitable for
the detailed spatial interaction and the corresponding three-
dimensional geometry information in host–guest complex study
gives rise to the induced circular dichroism (ICD) signals at wave-
lengths absorbed by the chromophore, and the sign of ICD signals
mainly depends on the orientation of transition dipole moment
of chromophore with respect to the axis of CD [14]. As seen from
Supplementary Figure S8, the circular dichroism spectra of hosts 1
−
1
−1
and 2 displayed the weak (|ꢀε| < 0.5 M cm ), but opposite, ICD
signals; that is, host 1 gave positive ICD signals but host 2 negative
signals. This result can be rationalized by our previous report where
the side arm of host 2 was self-included in, but that of host 1 located
outside the ˇ-CD cavity [15]. In addition, hosts 3 and 4 gave weak,
[16]. Fig. 4 gave the ROESY spectrum of host 4 in D O, which
2
displayed the NOE correlations between H5/H6 protons of ˇ-CD
and protons of the naphthalene moiety of host 4 (cross-peaks
A). In addition, no NOE correlation between H3 protons of ˇ-CD
Fig. 6. ROESY spectrum of 1/(−)-borneol ([1] = [(−)-borneol] = 1.0 mM) in D2O (3% DMSO) with a mixing time of 280 ms at 298.15 K. (For interpretation of the references to
color in this figure legend, the reader is referred to the web version of this article.)

N. Li et al. / Thermochimica Acta 576 (2014) 18–26
23
Fig. 7. ROESY spectrum of 4/(−)-borneol ([4] = [(−)-borneol] = 1.0 mM) in D2O (3% DMSO) with a mixing time of 250 ms at 298.15 K. (For interpretation of the references to
color in this figure legend, the reader is referred to the web version of this article.)
and naphthalene protons could be observed. It is well-known that
H5/H6 protons are located near the narrow side of the CD cavity,
whereas H3 protons are near the wide side. This information indi-
cated that the naphthalene moiety of 4 shallowly penetrated into
the cavity of ˇ-CD from the narrow side. In contrast, no NOE cor-
relation between naphthalene protons of 3 and interior protons
assigned to NOE correlations between Hh protons of (−)-borneol
with H3/H5/H6 protons of ˇ-CD. Peaks D and F were assigned
to NOE correlations between Hc/Hd protons of (−)-borneol and
H3/H5/H6 protons of ˇ-CD, where H5/H6 protons gave stronger
NOE correlations than H3 protons. The peak E was assigned to
NOE correlations between He protons of (−)-borneol and H5/H6
protons of ˇ-CD. The peak G was assigned to NOE correlations
(
H3/H5/H6) of ˇ-CD cavity could be observed, indicating the naph-
thalene substituent of 3 was located outside the ˇ-CD cavity. In our
previous report, host 2 adopted a self-included conformation but
host 1 adopted a self-excluded one [15]. Therefore, we deduced
that host CDs without triazole group would form self-included
monomer, but the introduction of triazole group would prevent
the self-penetration of substituent moieties into CD cavities.
Fig. 5 shows the ROESY spectrum of an equimolar mixture of
host 2 with (−)-borneol. The cross-peak H was assigned to NOE
correlation between H3/H5 protons of ˇ-CD and protons of the
quinoline moiety. This indicated that the quinoline moiety was still
located in the ˇ-CD cavity after the guest inclusion. Meanwhile,
we also found that the strength of NOE correlations of quinoline
protons of 2 with H5/H6 protons of ˇ-CD became stronger than
that with H3 protons. Hence, we indicated that the quinoline moi-
ety of 2 partly moved to the narrow opening of ˇ-CD. In addition,
cross-peaks between protons of (−)-borneol and interior protons
of ˇ-CD cavity were marked as peaks B, C, D, E, F, and G. Among
them, the peak B was assigned to NOE correlations between Hg
protons of (−)-borneol and H3/H5 protons of ˇ-CD. The peak C was
between Ha/H protons of (−)-borneol and H3/H5/H6 protons of ˇ-
b
CD, where H3 protons gave stronger NOE correlations than H5/H6
protons. According to these NOE signals, we deduced that host 2
adopted a co-inclusion mode upon complexation with (−)-borneol,
where the guest molecule entered the ˇ-CD cavity from the wide
side and the quinoline moiety was self-included in the ˇ-CD cavity
from the narrow side.
The ROESY spectrum of an equimolar mixture of host 1 with
(−)-borneol was shown in Fig. 6. We could also see NOE correlation
between protons of (−)-borneol and interior protons of ˇ-CD cavity.
The cross-peak I was assigned to NOE correlations between Hg pro-
tons of (−)-borneol and H3/H5/H6 protons of ˇ-CD, and the cross-
peak J was assigned to NOE correlations between H protons of (−)-
h
borneol and H3/H5 protons of ˇ-CD. Moreover, peaks K and M were
assigned to NOE correlations between Hc/H protons of (−)-borneol
d
and H5/H6 protons of ˇ-CD, and the peak L was assigned to NOE
correlations between He protons of (−)-borneol and H5/H6 pro-
tons of ˇ-CD. The peak N was assigned to NOE correlations between
Ha/Hb protons of (−)-borneol and H3/H5 protons of ˇ-CD, where

2
4
N. Li et al. / Thermochimica Acta 576 (2014) 18–26
Fig. 8. (a) Possible binding modes of hosts 2 and 1 with (−)-borneol. (b) Structures of 2/(−)-borneol and 1/(−)-borneol based on molecular modeling study. The structures
were colored by atom type: gray, carbon atoms; white, hydrogen atoms; red, oxygen atoms; blue, nitrogen atoms. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)
H3 protons gave stronger NOE correlations than H5 protons. As
mentioned previously, host 1 was not self-included. Therefore,
we deduced that the (−)-borneol guest entered the ˇ-CD cavity
through the wide side, and the substituent moiety of host 1 was
still located out of the ˇ-CD cavity. The similar binding mode was
also observed in the inclusion complexation of host 3. The possible
molecular binding modes of hosts 2 and 1 with (−)-borneol were
depicted in Fig. 8(a).
to 1.1 [17–21]. Moreover, the CPK (Corey–Pauling–Koltun) molec-
ular modeling study showed that each ˇ-CD cavity could only
accommodate one borneol or camphor molecule (Fig. 8b). There-
fore, a fixed 1:1 binding stoichiometry was used in the curve-fitting
analysis of calorimetric titration.
3.4. Binding ability
Fig. 7 gave the ROESY spectrum for the complex between host
4
and (−)-borneol. The cross-peak O corresponded to NOE corre-
As reported, substituents of host CDs were not protonated
lations between Hg protons of (−)-borneol and H3/H5/H6 protons
of ˇ-CD, and the cross-peak P was assigned to NOE correlations
between Hh protons of (−)-borneol and H3/H5/H6 protons of ˇ-
CD. Meanwhile, peaks Q and S were assigned to NOE correlations
at a neutral environment [15,22]. Therefore, non-covalent weak
interactions such as hydrophobic interaction, van der Waals inter-
action, and hydrogen bonding should be main driving forces of
the host–guest inclusion complexation, and the strength of these
weak interactions are greatly governed by the size/shape fitting
efficiency between host and guest [11]. As shown in Table 1, bind-
ing abilities of hosts 1–4 toward borneol were higher than toward
camphor. Possessing a hydroxyl group at the C-2 position, borneol
could give stronger hydrogen bond interactions with numerous
hydroxyl groups of CD cavities. While, hydrogen bond interactions
should be weaker between camphor, which possesses a carbonyl
group at the C-2 position, and host CDs. This result was also
verified by thermodynamic data, where most of host/borneol bind-
ings showed more negative enthalpic changes than host/camphor
ones.
between Hc/H protons of (−)-borneol and H5/H6 protons of ˇ-CD,
d
and the peak R was assigned to NOE correlations between He pro-
tons of (−)-borneol and H5/H6 protons of ˇ-CD. In addition, the
peak T was assigned to NOE correlations between Ha/H protons
b
of (−)-borneol and H3/H5/H6 protons of ˇ-CD, where H3 protons
gave stronger NOE correlations than H5/H6 protons. Moreover, we
could still find the NOE correlations (peak U) between protons of
ˇ-CD and protons of the naphthalene moiety of host 4, thus we
could deduce that naphthalene moiety of 4 still partially included
into the cavity of ˇ-CD from the narrow opening and the guest
molecule entered the cavity of host 4 from the wide opening.
Compared with native ˇ-CD, hosts 1–4 exhibited larger KS
values toward borneol and camphor. KS values for bindings of
hosts 1–4 were 1.1–6.4 times higher toward borneol and 1.3–3.5
times higher toward camphor than corresponding values of ˇ-CD.
To visualize and easily discuss the binding ability, the order of
3
.3. Binding stoichiometry
In ITC experiments, all of host–guest binding gave a 1:1 stoichi-
ometry with “N” values in the curve fitting results varying from 0.9

N. Li et al. / Thermochimica Acta 576 (2014) 18–26
25
were more negative than differential entropic changes
◦
◦
(TꢀS
− TꢀS ˇ-CD). Therefore, it may infer that enhanced
Hosts 1–4
binding abilities of hosts 1–4 toward with borneol and camphor
were mainly attributed to favorable enthalpic contributions but
not entropic contributions. In another word, it were van der Waals
interactions and hydrogen bonds, but not hydrophobic interactions
or desolvation effects, that led to stronger binding abilities of hosts
1–4 than native ˇ-CD.
4. Conclusion
In the present investigation, studies of binding behaviors of two
ˇ-CD derivatives bearing triazole groups and their analogs with-
out triazole groups demonstrated that host CDs showed higher
binding abilities than native ˇ-CD. Thermodynamically, the bind-
ing behaviors of four host CDs toward guest molecules were
entirely driven by favorable enthalpic changes, accompanied by
unfavorable entropic changes. In addition, the hydrogen-bonding
interactions and van der Waals interactions were the main driven
forces governing the host–guest binding. Moreover, the formation
of self-included monomers could not only increase binding abil-
ities but also strengthen desolvation effects of hosts and guests
to some extent because the self-included conformation led to the
better induced-fit effect in the host–guest co-inclusion binding
mode.
Fig. 9. Enthalpic (ꢀH host − ꢀH◦ ˇ-CD) and entropic changes (TꢀS host − TꢀS ˇ-CD)
◦
◦
◦
for inclusion complexations of (± )-borneol and (± )-camphor with hosts 1–4 in
phosphate aqueous buffer solutions (pH = 7.20, I = 0.1 M, 3% DMSO) at 298.15 K.
complex stability constants for (± )-borneol and (± )-camphor by
native ˇ-CD and hosts 1–4 were shown as follows:
Acknowledgments
(−)-Borneol: 4 > 2 > 1 > 3 > ˇ-CD;
(+)-Borneol: 4 > 2 > 1 > 3 > ˇ-CD;
(−)-Camphor: 4 > 2 > 1 > 3 > ˇ-CD;
(+)-Camphor: 4 > 2 > 1 > 3 > ˇ-CD.
We thank NNSFC (21272125 and 21102075), Program for New
Century Excellent Talents in University (NCET-10-0500), and the
Specialized Research Fund for the Doctoral Program of Higher Edu-
cation (20110031120014) for financial support.
It was interesting to note that, host 2 (or 4) gave obviously
stronger binding abilities toward guest molecules than host 1 (or
). In the previous section, 2D NMR studies demonstrated that
Appendix A. Supplementary data
3
host 2 (or 4) adopted a co-inclusion binding mode upon complex-
ation with guest molecules. This binding mode not only decreased
the effective volume of ˇ-CD cavity to some extent and thus led
to the higher size-fit efficiency between host and guest [23], but
also enabled additional non-covalent interactions between the
substituent group and the accommodated guest molecules. On
the other hand, the existence of triazole moiety in host 1 (or 3)
increased the distance from the substituent group to the accommo-
dated guest molecule. Due to the joint contribution of these factors,
host CDs without triazole moieties showed higher binding abilities
than host CDs with triazole moieties.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tca.2013.11.021.
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